Gynecomastia is listed as a rare side effect of numerous antihypertensive medications (Table). It occurs in <1% of persons who take these medications and in most cases the incidence is no more common than that seen with placebo. However, one antihypertensive medication that is commonly associated with gynecomastia is spironolactone.
Table.
Antihypertensive Medications Associated With Gynecomastia
| Commonly Associated |
| Potassium sparing diuretics |
| Spironolactone |
| Rarely Associated |
| Calcium channel blockers |
| Nifedipine |
| Amlodipine |
| Diltiazem |
| Verapamil |
| Angiotensin‐converting enzyme inhibitors |
| Captopril |
| Enalapril |
| Alpha receptor blockers |
| Doxazosin |
| Prazosin |
| Centrally acting agents |
| Clonidine |
| Methyldopa |
| Reserpine |
Spironolactone‐associated gynecomastia has been a recognized entity for more than 40 years. It has become more pertinent in the past 5 years with the widespread use of spironolactone for patients with congestive heart failure or resistant hypertension. Gynecomastia and/or breast pain was reported as an adverse event by 10% of men who received spironolactone at a dose of 25 mg/d in the Randomized Aldactone Evaluation Study (RALES). 1 Spironolactone‐associated gynecomastia is dose‐dependent and has a reported incidence of up to 52% with the use of a dose of 150 mg/d. It is also related to duration of therapy, and is usually reversible after discontinuation of the drug.
There are several other endocrine side effects commonly reported with the use of spironolactone including impotence, decreased libido, and menstrual abnormalities. Gynecomastia and these other endocrine effects are the result of an alteration of the testosterone‐estrogen ratio in favor of estrogen. 2 Specifically, spironolactone blocks androgen production by inhibiting enzymes in the testosterone synthetic pathway (i.e., 17α‐hydroxylase and 17,20‐desmolase), blocks testosterone and dihydrotestosterone from binding to their receptors, increases serum free estradiol by displacing estradiol from sex hormone binding globulin, and increases peripheral conversion of testosterone to estradiol.
To address this problem, a selective aldosterone antagonist, eplerenone, has been developed. Eplerenone does not cause gynecomastia even in patients who had previously developed this side effect while on spironolactone. The selectivity of eplerenone for the aldosterone receptor over other steroid receptors is thought to be the result of replacement of a 17α‐thioacetyl group with a carbomethoxy group. 3 Consequently, in the Eplerenone Post‐Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) 4 the incidence of gynecomastia and other endocrine side effects in the treatment arm was the same as the incidence in the placebo arm. The principal findings of this study were a 15% relative risk reduction (2.3% absolute risk reduction) of all‐cause mortality and a 17% relative risk reduction (2.3% absolute risk reduction) of cardiovascular death with the use of eplerenone. These results are not as impressive as those reported with spironolactone in the RALES study, although there are important differences in the study designs. Eplerenone has not been compared head to head with spironolactone in any large clinical trial and it is considerably more expensive than spironolactone. Thus, the editorial accompanying the EPHESUS report recommended against using eplerenone (for the treatment of congestive heart failure in the proper clinical context) without first trying spironolactone. 5
Gynecomastia is a common problem encountered during therapy with spironolactone. Despite the availability of eplerenone, a selective aldosteroneantagonist that is not associated with endocrine side effects, spironolactone should still be the aldosterone antagonist of first choice for the treatment of heart failure or hypertension because it has well documented efficacy and is less costly. Nevertheless, if gynecomastia or other troubling endocrine side effects develop with the use of spironolactone, eplerenone would be an appropriate substitute.
References
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